Cited by 960
University of Tsukuba
Publishes on Drug Transport and Resistance Mechanisms, DNA and Nucleic Acid Chemistry, Pancreatic and Hepatic Oncology Research. 14 papers and 1.3k citations.
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To elucidate the mechanism(s) of cisplatin resistance, we have characterized a human non-small cell lung cancer cell line (PC-9/CDDP) selected from the wild type (PC-9) for acquired resistance to cisplatin. PC-9/CDDP demonstrated 28-fold resistance to cisplatin, with cross resistance to other chemotherapeutic drugs including chlorambucil (X 6.3), melphalan (X 3.7) and 3-[(4-amino-2-methyl-5-pyrimidinyl)]methyl-1-(2-chloroethyl)-1-nitros our ea (ACNU) (x 3.9). There was no expression of mdr-1 mRNA in either wild-type or resistant cells. The mRNA and protein levels of glutathione S-transferase (GST) pi were similar in the two lines. A GST-mu isozyme was present in equal amounts and the activities of selenium-dependent and independent glutathione peroxidase and glutathione reductase were unchanged. The mRNA level of human metallothionein IIA and the total intracellular metallothionein levels were reduced in the resistant cells. Significantly increased intracellular glutathione (GSH) levels were found in the resistant cells (20.0 vs 63.5 nmol/mg protein) and manipulation of these levels with buthionine sulfoximine produced a partial sensitization to either cisplatin or chlorambucil. Increased GSH probably also played a role in determining cadmium chloride resistance of the PC-9/CDDP, even though this cell line had a reduced metallothionein level. Also contributing to the cisplatin resistance phenotype was a reduced intracellular level of platinum in the PC-9/CDDP. Thus, at least two distinct mechanisms have been selected in the resistant cells which confer the phenotype and allow degrees of cross resistance to other electrophilic drugs.
Strain TP-A0248 which produces two new Cdc25B tyrosine phosphatase inhibitors and also possessing antifungal activity, designated nocardiones A (1) and B (2), was considered to belong to the genus Nocardia on the basis of literature comparison of chemotaxonomic properties. The nocardiones were isolated by solvent extraction of fermentation broth of Nocardia sp. TP-A0248 and purified by the conventional column chromatography. Spectroscopic studies led to determination that 1 and 2 belong to a class compound of naphtho[1,2-b]furan-4,5-diones. Compound 1 inhibited the activity of Cdc25B, PTP1B and FAP-1 protein tyrosine phosphatases at a concentration of 10 microM. It also showed moderate in vitro antifungal and cytotoxic activity.